ABSTRACT Traumatic brain injury (TBI) afflicts over 1.7 million persons per year in the U.S. alone, resulting in substantial economic burden annually. It is well known that the mechanical insult from TBI initiates immediate cellular death (i.e. primary injury) and stimulates a broad range of complex deleterious signaling cascades (i.e. secondary injury). Altered gene regulation is at the crux of the secondary injury signaling cascade, which generates silencing of genes critical for cell survival, neural plasticity, and homeostatic maintenance, as well as activation of inflammatory and cell death genes. Our long-term goal is to develop clinically translatable therapeutics that minimize neuroinflammation following a TBI. Here, our primary objective is to inhibit deleterious epigenetic modifications that occur following TBI through nanoparticle based delivery of small molecule drugs that inhibit histone deacetylases (HDACs), which we predict will alleviate neuropathology toward functional recovery in a murine model. Acetylation of histones is one epigenetic modification that enables relaxation of chromatin to facilitate gene expression. In contrast, HDACs remove acetylation points, allowing for chromatin compaction and gene silencing. After TBI, HDAC levels are markedly increased. Thus, HDACs are a key cellular target contributing to the pro-inflammatory and anti-neuroplastic microenvironment that characterizes the second phase injury response in TBI. Recently, numerous preclinical studies in TBI have shown that early administration of HDAC inhibitors (HDACis) significantly decreases the neurological damage, as evidenced by increased neural survival, decreased inflammatory markers, and improved functional outcomes. However, a key limitation in translating HDACi treatment to the clinic is the need for supratherapuetic dosing, which contributes to undesired systemic side effects (i.e. neuropathic pain). Recently, the Sirianni group developed a novel strategy to enable very high loading of acidic HDACis within polymeric nanoparticles composed of poly(lactic acid)-poly(ethylene glycol) (PLA-PEG). Importantly, the Stabenfeldt group has demonstrated a transient window inside 12hrs after TBI where marked NP accumulation occurs within the injury penumbra; these studies identify a unique opportunity for synergistically enhancing NP delivery by timing treatment appropriately after injury. Combining these key innovations will enable evaluation of HDACi NPs as an intervention for TBI. Our specific aims are to (1) develop a library of HDACi NPs directed at minimizing neuroinflammation, (2) evaluate the impact HDACi NP intervention has on minimizing aberrant pathology following TBI toward improving functional recovery. We expect that completion of these aims will simultaneously advance HDACi as a therapeutic strategy and improve our understanding of NP delivery in TBI.